Preterm labor resulting in the delivery of a premature infant is a complex problem with an enormous impact on individuals, families and society. 500,000 children will be born prematurely in the U.S. this year, and worldwide 5 million will die of prematurity and its complications. It is the single largest contributor to DALYs, disability adjusted life years, a measure of the lifetime impact of a disease. Despite the importance of the problem and its disproportionate occurrence in poor and minority populations, insufficient resources have been targeted to discover its underlying etiology. The largest single cause of prematurity is spontaneous preterm labor, and suspected triggers for this include infection, stress, poor nutrition and genetic factors. Numerous family and twin studies provide strong evidence that genetic factors underlie about 40% of the risk for prematurity. The single best predictor for preterm delivery is a previous preterm birth. A major challenge in studying genetic factors in prematurity is that the risk could reside either in the mother and her uterus or in the infant/placenta. Thus, any approach to studying preterm birth should account for both infant and maternal risk, environmental covariates and interactions. The Danish National Birth Cohort Study is a well established, prospective cohort study that has the advantage of enrolling women early in pregnancy when the outcome is still unknown, so that bias in data collection and sampling is minimized. The Danish study has followed over 96,000 women beginning in the first trimester of pregnancy and has extensive biological and epidemiologic data on the outcomes of both mother and child. In this proposal, we will do a genome-wide case/control analysis using 1,000 very well characterized cases of spontaneous preterm birth, with biological samples on the mother and infant, drawn from the Danish National Birth Cohort Study. These will be matched to 1,000 mother/infant controls, born at 39 or 40 weeks gestation. Extensive epidemiologic variables will be used as covariates in the analysis. To replicate positive findings, we can access the deep resource of additional controls from the same Danish National Birth Cohort Study as well as more than 1,000 mother/father/preterm infant triads available from a large sample collection in the United States, and a further 1,000 U.S. case/controls enriched for African-Americans, a population known to have high rates of preterm labor. Positive results involving environmental factors can be further investigated, as the Danish cohort has maternal serum samples from early and mid pregnancy, as well as additional epidemiologic and outcome data. The study should enable a better understanding of the biology of parturition, identify common genetic factors that play a role in prematurity and suggest environmental modifications that can prolong gestations, with the goal of improving both neonatal and adult outcomes.